9Z1W
Cryo-EM structure of human TRPM4 channel in complex with calcium and TPPO at 37 degrees Celsius (consensus)
This is a non-PDB format compatible entry.
Summary for 9Z1W
| Entry DOI | 10.2210/pdb9z1w/pdb |
| EMDB information | 73754 |
| Descriptor | Transient receptor potential cation channel subfamily M member 4, CALCIUM ION, oxotri(phenyl)-lambda~5~-phosphane (3 entities in total) |
| Functional Keywords | ion channel, trp channel, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 539259.70 |
| Authors | Jinhong, H.,Wei, L.,Juan, D. (deposition date: 2025-11-04, release date: 2026-06-10, Last modification date: 2026-07-01) |
| Primary citation | Hu, J.,Ievleva, S.,Park, S.J.,Lee, J.,Cheng, J.,O'Dea, G.,Sheng, J.,Du, J.,Lu, W. Temperature and intrinsic Ca 2+ reshape TRPM4 pharmacology. Nat.Struct.Mol.Biol., 33:973-984, 2026 Cited by PubMed Abstract: Proteins operate in dynamic environments where ions, lipids and temperature collectively define their properties, yet most studies rely on simplified conditions that overlook these intrinsic variables. Here we show two such factors-temperature and Ca-remodel the function and pharmacology of TRPM4, an ion channel implicated in cardiac conduction, immune regulation, cancer and intestinal-fluid homeostasis. At physiological temperature and Ca, TPPO-previously considered a selective TRPM5 inhibitor inactive toward TRPM4-potently activates TRPM4, revealing strong synergy among temperature, Ca and ligand binding. By contrast, Necrocide-1, a necroptotic activator targeting the same binding pocket, defies this logic: it opens TRPM4 without Ca but is antagonized by Ca. Meanwhile, the inhibitors NBA and CBA engage a nearby pocket, locking the channel in a non-conductive pre-open state. Our findings highlight that even rigid binding pockets can exhibit temperature-dependent ligand recognition, revealing hidden pharmacology and informing selective, environment-aware therapeutic strategies. PubMed: 42265346DOI: 10.1038/s41594-026-01818-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.86 Å) |
Structure validation
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